Phase response curves for home remedies to treat circadian misalignment

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DESCRIPTION (provided by applicant): In modern society, there are a number of situations in which human circadian rhythms are misaligned with the desired sleep/wake schedule. Jet travel, night shift work, early morning shift work and merely returning to a normal work or school schedule either on Monday morning after sleeping later on the weekend or after being on vacation can all result in circadian misalignment. This misalignment produces a wide range of symptoms including daytime sleepiness, decreased alertness, insomnia, chronic partial sleep deprivation, and gastrointestinal distress. Both bright light and melatonin are able to reset or phase shift the circadian clock, and have been used to help people adapt to their desired sleep/wake schedule. The commercial, over-the-counter availability of a wide range of melatonin doses and light boxes highlights the consumer's desire for simple, non-invasive, at-home treatments to treat circadian-related sleep disorders. Recently it has been demonstrated that the circadian system primarily detects light using a novel, blue-light-sensitive photoreceptor, although the rods and cones also provide some input. Industry has capitalized on this discovery, and blue light boxes are now available. However, in order to obtain maximum benefit from melatonin pills or light boxes it is essential to know their optimal administration time. Phase response curves (PRCs) describe the phase shifting response to a specific stimulus when it is presented at different times throughout the 24-h day. We propose to generate PRCs to over-the-counter, commercially available phase shifting products: melatonin pills and light boxes. Therefore, the results of our studies will yield direct practical recommendations. We will generate 4 PRCs: 1) 0.5 mg melatonin, 2) 3.0 mg melatonin, 3) bright white light, and 4) medium intensity blue light. We will use a novel, efficient protocol in which subjects free-run through an ultradian light-dark/wake-sleep schedule (4 h days), and we will apply melatonin or light at various points throughout the circadian cycle. We will use the endogenous melatonin rhythm as a marker of the circadian clock, to calculate phase shifts and the time of the administration of the melatonin or light. The PRCs will tell us when to administer these phase shifting stimuli to achieve the maximum phase shift in the desired direction, and also times at which use of these products would induce a phase shift in the wrong direction and should be avoided. This information is needed so that professionals can make the best recommendations to patients and other consumers. In addition, comparison of the PRCs may also reveal information about the human circadian system, such as the relative phase shifting abilities of melatonin and light or the relative contribution of photoreceptors to the circadian system.